Background and Significance: Durable developments in Nanomedicine and Nanosafety rely on our understanding of interactions occurring at the interface between the nanoparticles and biological targets. It is now well-established that “corona” of proteins and other biomolecules forms at such bionanointerface. Consequently, this interface is closely linked to the in vivo fate and behaviour of nanomaterials, primarily through multilayered interactions with various receptors expressed on the cell membrane in a given organ (e.g., the liver) and biological barriers (e.g., blood brain barrier). Hence, the potential to develop these systems depends on our capacity to measure these interactions in a meaningful manner for systems of real interest. In essence, this means to study interactions between nanoparticles that do not contain any label (labeling is mainly for research purpose) and cells that express relevant receptors (such as receptors in liver cells) in realistic biological milieu (such as human plasma). The absence of such understanding, and well defined means to measure their interactions (in realistic milieu) has lead existing nanoparticle targeting strategies, that seem promising when tested under non-physiological conditions, to fail when tested in vivo, where multiple competitive interactions occur, and where non-specific binding in many cases blocks the targeting functionality of the nanoparticles, rendering them inactive. The absence of a realistic and cost effective means to screen these properties has (in part) lead to slow regulatory approval and adoption.

Summary description of the project objectives: Together, NUID UCD and Attana AB are developing a cost effective, high throughput screening platform for characterization of the bionanointerface and its cell-binding partners, to address a range of important questions currently hampering the implementation of nanotechnologies, both in medicine and generally in consumer products. This project aims to develop a cost effective, high throughput screening platform based on Attana Cell 200 for (a) characterization of the bionanointerface and identification of key molecular details for nanoparticle-cell interactions, and (b) tracking the interaction of nanoparticles with biological cells in the presence of a realistic milieu. Together these would provide the first high throughput label free approach to the whole arena. While all systems could then be evaluated, as an example, an explicit aspiration involving the highest level of achievement would involve the capacity to screen nanoparticles (quickly and cheaply) for likely accumulation in the liver, or another key organ. This would be the first such achievement, and may be expected to have substantive and durable impact on the field in general.We intend to achieve this overarching objective within the lifetime of this project, and consider we have made substantial gain along this path.

Description of the work performed and description of the main results achieved so far: So far much of the work carried out has been within three broad categories. Firstly, core assets to enable the project have been developed (including nanoparticle libraries for standardization of methods, cell libraries to enable nanoparticle receptor interaction studies and others). While these are key to the success of the project, they are also believed to have a longer term and durable value in the field as the approach becomes more widely adopted. Secondly, we have made all the (mostly baseline) studies as envisaged in the original program, and made necessary adaptations of systems and instrument to allow for deployment in the nanotechnology arena. This involved experiments that establish our capacity to measure interactions between biological milieu and nanoparticles, as well as those between nanoparticle-biomolecule complexes and cells. This has established the feasibility of our overall intentions. Finally, we have identified all technical difficulties within the original plan, and created a sort of ‘work plan of difficulty’ that constitute the major barriers to our final success. It is this plan we intend to address in the second part of the project, after mid term.

Expected final results and their potential impact and use: We consider the outcomes, and their impact to have the highest order of impact. While those impacts will be broadly distributed across the whole field, we will measure our overall success by the achievement of two key outcomes. Firstly, we believe we will for the first time offer a (reproducible and widely usable) means to fully characterize (in a biologically meaningful manner) nanoparticle surface interactions, filling a major gap in current scientific understanding and regulatory approval. We believe this will make low cost screening and Phase 1 approvals much more accessible. Secondly, we will (for the first time) be able to predict (screen for) likely bio-distributions of nanoparticles in organs, as well as (for example tumor) targets. To make this concrete, we believe we will be able to give broad parametric predictions for the likely accumulation of nanoparticles in the liver. Since undesirable liver accumulation (and consequent toxicity) is a major roadblock to commercialization and exploitation, this is expected to have a significant impact, across the field. Project Website: http://www.nanoclassifier.eu/Project Contacts: Project-Office@NanoClassifier.eu